α- and β-amino acid hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors

ABSTRACT

α-and β-amino acid hydroxyethylamino sulfonyl urea derivative compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent appln. Ser. No.09/731,911 filed Dec. 8, 2000 (now allowed) now U.S. Pat. No. 6,403,585,which was a continuation of U.S. patent appln. Ser. No. 09/345,739 filedJul. 1, 1999 (now U.S. Pat. No. 6,211,176), which was a continuation ofU.S. patent appln. No. 08/709,069 filed Sep. 6, 1996 (now U.S. Pat. No.6,022,872), which was a divisional of U.S. patent appln. Ser. No.07/968,712, filed Oct. 30, 1992 (now U.S. Pat. No. 5,578,606). Each ofthese applications is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to retroviral protease inhibitors and,more particularly, relates to novel compounds and a composition andmethod for inhibiting retroviral proteases. This invention, inparticular, relates to sulfonyl urea derivatives of hydroxyethylamineprotease inhibitor compounds, a composition and method for inhibitingretroviral proteases such as human immunodeficiency virus (HIV) proteaseand for treating a retroviral infection, e.g., an HIV infection. Thesubject invention also relates to processes for making such compounds aswell as to intermediates useful in such processes.

2. Related Art

During the replication cycle of retroviruses, gag and gag-pol geneproducts are translated as proteins. These proteins are subsequentlyprocessed by a virally encoded protease (or proteinase) to yield viralenzymes and structural proteins of the virus core. Most commonly, thegag precursor proteins are processed into the core proteins and the polprecursor proteins are processed into the viral enzymes, e.g., reversetranscriptase and retroviral protease. It has been shown that correctprocessing of the precursor proteins by the retroviral protease isnecessary for assembly of infectious virons. For example, it has beenshown that frameshift mutations in the protease region of the pol geneof HIV prevents processing of the gag precursor protein. It has alsobeen shown through site-directed mutagenesis of an aspartic acid residuein the HIV protease that processing of the gag precursor protein isprevented. Thus, attempts have been made to inhibit viral replication byinhibiting the action of retroviral proteases.

Retroviral protease inhibition may involve a transition-state mimeticwhereby the retroviral protease is exposed to a mimetic compound whichbinds to the enzyme in competition with the gag and gag-pol proteins tothereby inhibit replication of structural proteins and, moreimportantly, the retroviral protease itself. In this manner, retroviralreplication proteases can be effectively inhibited.

Several classes of compounds have been proposed, particularly forinhibition of proteases, such as for inhibition of HIV protease. Suchcompounds include hydroxyethylamine isosteres and reduced amideisosteres. See, for example, EP 0 346 847; EP 0 342,541; Roberts et al,“Rational Design of Peptide-Based Proteinase Inhibitors”, “Science”,248, 358 (1990); and Erickson et al, “Design Activity, and 2.8 Å CrystalStructure of a C₂ Symmetric Inhibitor Complexed to HIV-1 Protease,”Science, 249, 527 (1990).

Several classes of compounds are known to be useful as inhibitors of theproteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198;U.K. 2,184,730; G.B. 2,209,752; EP 0 264 795; G.B. 2,200,115 and U.S.SIR H725. Of these, G.B. 2,200,115, GB 2,209,752, EP 0 264,795, U.S. SIRH725 and U.S. 4,599,198 disclose urea-containing hydroxyethylamine renininhibitors. G.B. 2,200,115 also discloses sulfamic acid-containinghydroxyethylamine renin inhibitors, and EP 0264 795 discloses certainsulfamic acid-containing hydroxyethylamine renin inhibitors. However, itis known that, although renin and HIV proteases are both classified asaspartyl proteases, compounds which are effective renin inhibitorsgenerally cannot be predicted to be effective HIV protease inhibitors.

BRIEF DESCRIPTION OF THE INVENTION

The present invention is directed to virus inhibiting compounds andcompositions. More particularly, the present invention is directed toretroviral protease inhibiting compounds and compositions, to a methodof inhibiting retroviral proteases, to processes for preparing thecompounds and to intermediates useful in such processes. The subjectcompounds are characterized as derivatives of hydroxyethylamino sulfonylurea inhibitor compounds.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, there is provided a retroviralprotease inhibiting compound of the formula:

or a pharmaceutically acceptable salt, prodrug or ester thereof wherein:

R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, alkoxycarbonyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxycarbonyl, heteroaroyl, hydroxyalkyl, aminocarbonyl,aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- anddisubstituted aminoalkanoyl radicals wherein the substituents areselected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkylradicals, or wherein said aminocarbonyl and aminoalkanoyl radicals aredisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen, radicals as defined for R³ or RΔSO₂—wherein RΔrepresents radicals as defined for R³; or R and R′ together with thenitrogen to which they are attached represent heterocycloalkyl andheteroaryl radicals;

R¹ represents hydrogen, —CH₂SO₂NH_(2,) —CH₂CO₂CH_(3,) —CO₂CH_(3,)—CONH_(2,) —CH₂C(O)NHCH_(3,) —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃),—C(CH₃)₂(SIOICH₃), —C(CH₃)₂(SIO₁₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals, and amino acid side chains selectedfrom asparagine, S-methyl cysteine and methionine and the sulfoxide (SO)and sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,norleucine, glutamine, threonine, glycine, allo-threonine, serine,O-alkyl serine, aspartic acid, beta-cyanoalanine and valine side chains;

R^(1′)and R¹Δ independently represent hydrogen and radicals as definedfor R¹, or one of R^(1′)and R¹, together with R¹ and the carbon atoms towhich R¹, R^(1′)and R¹ ′ are attached, represent a cycloalkyl radical;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO_(2,) —CN, —CF₃, —OR⁹ and—SR⁹, wherein R⁹ represents hydrogen and alkyl radicals, and halogenradicals;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals or the sulfone or sulfoxidederivatives thereof;

R⁴ represents hydrogen and radicals as defined by R³;

R⁶ represents hydrogen and alkyl radicals;

R⁷ and R⁷, independently represent hydrogen and radicals as defined forR³; amino acid side chains selected from the group consisting of valine,isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,glutamine, and t-butylglycine; radicals represented by the formulas—C(O)R¹⁶, —Co₂R¹⁶, —So₂R¹⁶, —SR¹⁶, —CoNR¹⁶R17, —CF₃ and —NR¹⁶R¹⁷; or R⁷and R⁷, together with the carbon atom to which they are attached form acycloalkyl-radical;

R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl,aralkyl/heterocycloalkyl and heteroaryl radicals and radicalsrepresented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷,CF₃ and NR¹⁶R¹⁷; wherein R¹⁶ and R¹⁷ independently represent hydrogenand radicals as defined for R³, or R¹⁶ and R¹⁷ together with a nitrogento which they are attached in the formula NR¹⁶R¹⁷ representheterocycloalkyl and heteroaryl radicals;

x represents 1 or 2;

n represents an integer of from 0 to 6;

t represents either 0, 1 or 2; and

Y represents O, S and NR¹⁵ wherein R¹⁵ represents hydrogen and radicalsas defined for R³.

Examples of compounds of the present invention as defined by Formula Iinclude:

1) 2S-[[(dimethylamino)acetyl]amino]-N-[3-[[[(2-hydroxy-1,1-dimethylethyl)amino]sulfonyl](3-methylbutyl)amino]-2R-hydroxy-1S-(phenylmethyl)-propyl]-3,3-dimethylbutanamide 2)N-[[[3S-[[2S-[[(dimethylamino)acetyl]amino]-3,3-dimethyl-1-oxobutyl]amino]-2R-hydroxy-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]-2- methylalanine 3)N-[[[3S-[[2S-[[(dimethylamino)acetyl]amino]-3,3-dimethyl-1-oxobutyl]amino]-2R-hydroxy-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]-2- methylalanine, methylester 4) 1-[[[[3S-[[2S-[[(dimethylamino)acetyl]amino]-3,3-dimethyl-1-oxobutyl]amino]-2R-hydroxy-4-phenylbutyl](4-pyridinylmethyl)amino]sulfonyl]-amino]cyclopentanecarboxylic acid 5)N-[[[3S-[[4-amino-1,4-dioxo-2S-[(2-quinolinyl-carbonyl)amino]butyl]amino]-2R-hydroxy-4-phenylbutyl](2-methylpropyl))amino]sulfonyl]-2- methylalanine 6)3-[[[[3S-[[2R-[[(dimethylamino)acetyl]amino]-3-methyl-3-(methylthio)-1-oxobutyl]amino]-2R-hydroxy-4-phenylbutyl](2-methylpropyl)amino]sulfonyl]- amino]-3-methylbutanoicacid 7) N-[[[2R-hydroxy-3S-[[3-[[[(4-methoxyphenyl)-methoxy]carbonyl]amino]-2R-methyl-1-oxopropyl]-amino]-4-phenylbutyl(3-methylbutyl)amino]sulfonyl]- 2-methylalanine 8)3-[[[[3S-[[2S-[[(dimethylamino)acetyl]amino]-3-methyl-1-oxopentyl]amino]-2R-hydroxy-4-phenyl-butyl][(4-fluorophenyl)methyl]amino]sulfonyl]- amino]-2-methylpropanoicacid 9) 1-[[[[2R-hydroxy-3S-[[3-methyl-1-oxo-2S-[[(phenylmethoxy)carbonyl]amino]butyl]amino]-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]amino]- cyclopentanecarboxylicacid 10)  1-[[[3S-[[4-amino-1,4-dioxo-2S-[(2-quinolinyl-carbonyl)amino]butyl]amino]-2R-hydroxy-4-phenylbutyl](3-methylbutyl)amino]sulfonyl]amino]- cyclopropanecarboxylicacid

A family of compounds of particular interest within Formula I arecompounds embraced by Formula II:

wherein:

R represents hydrogen, alkyl, alkenyl, cycloalkyl, hydroxyalkyl, aryl,aralkyl, aryloxyalkyl, heteroaryloxyalkyl, alkoxycarbonyl, alkoxyalkyl,aralkoxycarbonyl, alklcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,heteroaryloxy-carbonyl, heteroaroyl, aminocarbonyl, aminoalkanoyl, andmono- and disubstituted aminocarbonyl and mono- and disubstitutedaminoalkanoyl radicals wherein the substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, heterocycloalkyalkyl radicals, or where saidaminoalkanoyl radical is disubstituted, said substituents along with thenitrogen atom to which they are attached form a heterocycloalkyl orheteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, —CH₂SO₂NH_(2,) —CH₂CO₂CH_(3,) —CO₂CH_(3,)—CONH_(2,) —CH₂C(O)NHCH3, —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃),—C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals, and amino acid side chains selectedfrom asparagine, S-methyl cysteine and methionine and the sulfoxide (SO)and sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,norleucine, glutamine, threonine, glycine, allo-threonine, serine,O-methyl serine, aspartic acid, beta-cyanoalanine and valine sidechains;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —N_(2,) —C=N, CF₃, —OR⁹, —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals and the sulfone or sulfoxidederivatives thereof;

R⁴ represents hydrogen and radicals as defined by R³; R⁷ and R⁷′independently represent radicals as defined for R³; amino acid sidechains selected from the group consisting of valine, isoleucine,glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, andt-butylglycine; radicals represented by the formulas —C(O)R^(16,)—CO₂R¹⁶, —SO₂R^(16,) —SR¹⁶, —CONR¹⁶R_(17,) —CF₃ and —NR¹⁶R¹⁷; or R⁷ andR⁷, together with the carbon atom to which they are attached form acycloalkyl radical;

R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl,heterocycloalkyl and heteroaryl radicals and radicals represented by theformulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R^(17,) CF₃ and NR¹⁶R¹⁷;wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals asdefined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl andheteroaryl radicals;

n represents an integer of from 0 to 6;

A more preferred family of compounds within Formula II consists ofcompounds wherein:

R represents hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl,heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl,heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl,′heteroaryloxy-carbonyl, heteroaroyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstituted,aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents CH₂C(O)NHCH_(3,) C(CH₃)₂(SCH₃), C(CH₃)₂(S[O])CH₃),C(CH₃)₂(S[O]₂CH₃), alkyl, alkenyl and alkynyl radicals, and amino acidside chains selected from the group consisting of asparagine, valine,threonine, allo-threonine, isoleucine, tert-leucine, S-methyl cysteineand methionine and the sulfone and sulfoxide derivatives thereof,alanine, and allo-isoleucine;

R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents alkylradicals; and R³ represents alkyl, haloalkyl, alkenyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl and heteroaralkyl radicals;

R⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals;

R⁷ and R⁷, independently represent alkyl and aralkyl radicals ortogether with the carbon atom to which they are attached form acycloalkyl radical having from 3 to 8 carbon atoms;

R⁸ represents alkylcarbonyl, aryl, aroyl, aryloxy, aralkanoyl, cyano,hydroxycarbonyl, arylsulfonyl, alkylsulfonyl, alkylthio, hydroxyl,alkoxy, heteroaryl, dialkylaminocarbonyl, dialkylamino, cycloalkylamino,heterocyclylamino and alkoxycarbonyl radicals; and

n is an integer of from 0 to 6;

Of highest interest are compounds within Formula II wherein

R represents alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents CH₂C(O)NHCH_(3,) C(CH₃)₂(SCH₃), C(CH₃)₂(S[O]CH₃),C(CH₃)₂(S[O]₂CH₃), methyl, propargyl, t-butyl, isopropyl and sec-butylradicals, and amino acid side chains selected from the group consistingof asparagine, valine, S-methyl cysteine, allo-iso-leucine, iso-leucine,and beta-cyano alanine side chains;

R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl, 4-fluorobenzyl,2-naphthylmethyl and cyclohexylmethyl radicals;

R³ represents propyl, isoamyl, n-butyl, isobutyl, cyclohexyl,cyclohexylmethyl, benzyl and pyridylmethyl radicals;

R⁴ represents hydrogen and methyl, ethyl, i-propyl, propyl, n-butyl,t-butyl, 1,1-dimethylpropyl, cyclohexyl and phenyl radicals;

R⁷ and R^(7′)independently represent methyl, ethyl, propyl and butylradicals, or together with the carbon atom to which they are attachedform a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical;

R⁸ represents methylcarbonyl, phenyl, hydroxy, methoxy, cyano,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl, carboxyl, methoxycarbonyl, methylsulfonyl,methylthio, phenylsulfonyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or4-pyridyl N-oxide, N,N-dimethylamino, 1-piperidinyl, 4-morpholinyli4-(N-methyl)piperazinyl and 1-pyrrolidinyl.

Another family of compounds of particular interest within Formula I arecompounds embraced by Formula III:

wherein:

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, alkoxyalkyl,heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, andmono- and disubstituted aminocarbonyl and mono- and disubstitutedaminoalkanoyl radicals wherein the substituents are selected from alkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, heterocycloalkyalkyl radicals, or where saidaminoalkanoyl radical is disubstituted, said substituents along with thenitrogen atom to which they are attached form a heterocycloalkyl orheteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, —CH₂SO₂NH_(2,) —CH₂CO₂CH_(3,) —CO₂CH_(3,)—CONH_(2,) —CH₂C(O)NHCH_(3,) —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃),—C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals, and amino acid side chains selectedfrom asparagine, S-methyl cysteine and the sulfoxide (SO) and sulfone(SO₂) derivatives thereof, isoleucine, allo-isoleucine, alanine,leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine,glutamine, threonine, glycine, allo-threonine, serine, aspartic acid,beta-cyano alanine and valine side chains;

R^(1′)and R¹ independently represent hydrogen and radicals as definedfor R¹, or one of R¹ ′ and R¹Δ, together with R¹ and the carbon atoms towhich R¹, R¹′ and R¹Δ are attached, represent a cycloalkyl radical;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO_(2,) —C=N, CF₃, —OR⁹ and—SR⁹, wherein R⁹ represents hydrogen and alkyl radicals;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals and the sulfone or sulfoxidederivatives thereof;

R⁴ represents hydrogen and radicals as defined by R³; R⁷ and R⁷′independently represent radicals as defined for R³; amino acid sidechains selected from the group consisting of valine, isoleucine,glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, andt-butylglycine; radicals represented by the formulas —C(O)R¹⁶, —CO₂R¹⁶,—SO₂R^(16,) —SR¹⁶, —CONR¹⁶R¹⁷, —CF₃ and —NR¹⁶R¹⁷; or R⁷ and R⁷, togetherwith the carbon atom to which they are attached form a cycloalkylradical;

R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl,heterocycloalkyl and heteroaryl radicals and radicals represented by theformulas C(O)R^(16,) CO₂R¹⁶, SO₂R¹⁶, SR¹⁶, CONR¹⁶R¹⁷, CF3 and NR¹⁶R¹⁷;wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals asdefined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl andheteroaryl radicals;

n represents an integer of from 0 to 6;

A more preferred family of compounds within Formula III consists ofcompounds wherein R represents an arylalkanoyl, heteroaroyl,aryloxyalkanoyl, aryloxycarbonyl, alkanoyl, aminocarbonyl,mono-substituted aminoalkanoyl, or disubstituted aminoalkanoyl, ormono-or dialkylaminocarbonyl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

R¹ R¹′ and R¹ independently represent hydrogen and alkyl radicals havingfrom to about 4 carbon atoms, alkenyl, alkynyl, aralkyl radicals, andradicals represented by the formula —CH₂C(O)RΔ or —C(O)RΔ wherein RΔrepresents R³⁸, —NR³⁸R³⁹ and OR³⁸ wherein R³⁸ and R³⁹ independentlyrepresent hydrogen and alkyl radicals having from 1 to about 4 carbonatoms;

R² represents alkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogenand alkyl radicals; and

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, alkoxyalkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, aralkyl, heteroaryl and heteroaralkyl radicals;

R⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals, or R⁴ and R⁵ together with the nitrogenatom to which they are bonded from a heterocycloalkyl or heteroarylradical;

R⁷ and R⁷′ independently represent alkyl and aralkyl radicals ortogether with the carbon atom to which they are attached form acycloalkyl radical having from 3 to 8 carbon atoms;

R⁸ represents alkylcarbonyl, aryl, aroyl, aryloxy, aralkanoyl, cyano,hydroxycarbonyl, arylsulfonyl, alkylsulfonyl, alkylthio, hydroxyl,alkoxy, heteroaryl, dialkylaminocarbonyl, dialkylamino, cycloalkylamino,heterocyclylamino and alkoxycarbonyl radicals. of highest interest arecompounds of Formula III wherein:

R represents an arylalkanoyl, aryloxycarbonyl, heteroaroyl,aryloxyalkanoyl, alkanoyl, aminocarbonyl, mono-substitutedaminoalkanoyl, or disubstituted aminoalkanoyl, or mono-ordialkylaminocarbonyl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached represent aheterocycloalkyl or heteroaryl radical;

R¹, R¹′ and R¹ Δ independently represent hydrogen, methyl, ethyl,benzyl, phenylpropyl, —C(O)NH₂ and propargyl radicals;

R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl, 4-fluorobenzyl,2-naphthylmethyl and cyclohexylmethyl radicals;

R³ represents propyl, isobutyl, isoamyl, n-butyl, n-propyl, cyclohexyl,cyclohexylmethyl, benzyland pyridylmethyl radicals;

R⁴ represents hydrogen and methyl, ethyl, i-propyl, n-butyl, t-butyl,1,1-dimethylpropyl, cyclohexyl and phenyl radicals;

R⁷ and R⁷′ independently represent methyl, ethyl, propyl and butylradicals, or together with the carbon atom to which they are attachedform a cyclopropyl, cyclobutyl, cyclopentyl ov cyclohexyl radical;

R⁸ represents methylcarbonyl, phenyl, hydroxy, methoxy, cyano,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl, carboxyl, methoxycarbonyl, methylsulfonyl,methylthio, phenylsulfonyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or4-pyridyl N-oxide, N,N-dimethylamino, 1-piperidinyl, 4-morpholinyl,4-(N-methyl)piperazinyl and 1-pyrrolidinyl.

Another family of compounds of particular interest within Formula I arecompounds embraced by Formula IV:

wherein:

R represents hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl,aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, alkoxycarbonyl,aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl,cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl,aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, alkoxyalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl,radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and Rtogether with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, —CH₂SO₂NH_(2,) —CH₂CO₂CH_(3,) —CO₂CH_(3,)—CONH_(2,) —CH₂C(O)NHCH_(3,) —C(CH₃)₂(SH), —C(CH3)₂(SCH₃),—C(CH₃)₂(SC[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals, and amino acid side chains selectedfrom asparagine, S-methyl cysteine and methionine and the sulfoxide (SO)and sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,norleucine, glutamine, threonine, glycine, allo-threonine, serine,aspartic acid, beta-cyano alanine and valine side chains;

R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radicals, —NO₂, —CF₃ —OR⁹, —SR⁹, whereinR⁹ represents hydrogen and alkyl;

R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted.aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals and the sulfone or sulfoxidederivatives thereof;

R⁴ represents hydrogen and radicals as defined for R³;

R⁷ and R⁷′independently represent radicals as defined for R³; amino acidside chains selected from the group consisting of valine, isoleucine,glycine, alanine, allo-isoleucine, asparagine, leucine, glutamine, andt-butylglycine; radicals represented by the formulas —C(O)R¹⁶,—CO₂R^(16,) —SO₂R^(16,) —SR¹⁶, —CONR¹⁶R^(17,) —CF₃ and —NR¹⁶R¹⁷; or R⁷and R⁷, together with the carbon atom to which they are attached form acycloalkyl radical;

R⁸ represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl,heterocycloalkyl and heteroaryl radicals and radicals represented by theformulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶ SR¹⁶, CONR¹⁶R¹⁷ CF₃ and NR¹⁶R¹⁷;

wherein R¹⁶ and R¹⁷ independently represent hydrogen and radicals asdefined for R³, or R¹⁶ and R¹⁷ together with a nitrogen to which theyare attached in the formula NR¹⁶R¹⁷ represent heterocycloalkyl andheteroaryl radicals;

n represents an integer of from 0 to 6.

A more preferred family of compounds within Formula IV consists ofcompounds wherein

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl, alkyl,alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl,hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstitutedaminocarbonyl and mono- and disubstituted aminoalkanoyl radicals whereinthe substituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R¹ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, alkyl, alkenyl, and alkynyl radicals, and aminoacid side chains selected from the group consisting of asparagine,valine, threonine, allo-threonine, isoleucine, tert-leucine, S-methylcysteine and the sulfone and sulfoxide derivatives thereof, alanine, andallo-isoleucine;

R² representsialkyl, cycloalkylalkyl and aralkyl radicals, whichradicals are optionally substituted with halogen radicals and radicalsrepresented by the formula —OR⁹ and —SR⁹ wherein R⁹ represents hydrogenand alkyl and halogen radicals;

R³ represents alkyl, haloalkyl, alkenyl, alkoxyalkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl,heteroaryl and heteroaralkyl radicals;

R⁴ represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl,heceroaryl, aralkyl, heteroaralkyl, heterocycloalkyl andheterocycloalkylalkyl radicals; R⁷ and R⁷, independently represent alkyland aralkyl radicals or together with the carbon atom to which they areattached form a cycloalkyl radical having from 3 to 8 carbon atoms;

R⁸ represents alkylcarbonyl, aryl, aroyl, aryloxy, aralkanoyl, cyano,hydroxycarbonyl, arylsulfonyl, alkylsulfonyl, alkylthio, hydroxyl,alkoxy, heteroaryl, dialkylaminocarbonyl, dialkylamino, cycloalkylamino,heterocyclylamino and alkoxycarbonyl radicals; and

n represents an integer of from 0 to 6.

Of highest interest are compounds within Formula IV wherein

R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl,cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl,alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl,aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl,heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl,heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, heteroaroyl,aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyland mono- and disubstituted aminoalkanoyl radicals wherein thesubstituents are selected from alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl,heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical isdisubstituted, said substituents along with the nitrogen atom to whichthey are attached form a heterocycloalkyl or heteroaryl radical;

R′ represents hydrogen and radicals as defined for R³ or R and R′together with the nitrogen to which they are attached representheterocycloalkyl and heteroaryl radical;

R¹ represents hydrogen, methyl, propargyl, t-butyl, isopropyl andsec-butyl radicals, and amino acid side chains selected from the groupconsisting of asparagine, valine, S-methyl cysteine, allo-iso-leucine,iso-leucine, threonine, serine, aspartic acid, beta-cyano alanine, andallo-threonine side chains;

R² represents CH₃SCH₂CH₂—, iso-butyl, n-butyl, benzyl, 4-fluorobenzyl,2-naphthylmethyl and cyclohexylmethyl radicals;

R³ represents propyl, isobutyl, isoamyl, n-butyl, cyclohexyl,cyclohexylmethyl, benzyl and pyridylmethyl radicals;

R⁴ represents hydrogen and methyl, ethyl, i-propyl, n-propyl, n-butyl,t-butyl, 1,1-dimethylpropyl, cyclohexyl a phenyl radicals;

R⁷ and R⁷, independently represent methyl, ethyl, propyl and butylradicals, or together with the carbon atom to which they are attachedform a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical;

R⁸ represents methylcarbonyl, phenyl, hydroxy, methoxy, cyano,methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl, carboxyl, methoxycarbonyl, methylsulfonyl,methylthio, phenylsulfonyl, phenyl, 2-, 3- or 4-pyridyl, 2-, 3- or4-pyridyl N-oxide, N,N-dimethylamino, 1-piperidinyl, 4-morpholinyl,4-(N-methyl)piperazinyl and 1-pyrrolidinyl; and

n represents an integer of from 0 to 6.

As utilized herein, the term “alkyl”, alone or in combination, means astraight-chain or branched-chain alkyl radical containing from 1 toabout 10, preferably from 1 to 8, carbon atoms. Examples of suchradicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. Theterm lalkenyll, alone or in combination, means a straight-chain orbranched-chain hydrocarbon radial having one or more double bonds andcontaining from 2 to about 18 carbon atoms preferably from 2 to 8 carbonatoms. Examples of suitable alkenyl radicals include ethenyl, propenyl,1,4-butadienyl, 12-octadecene and the like. The term lalkynyll, alone orin combination, means a straight-chain hydrocarbon radical having one ormore triple bonds and containing from 2 to about 10 carbon atoms,preferably from 2 to 8 carbon atoms. Examples of alkynyl radicalsinclude ethynyl, propynyl, (propargyl), butynyl and the like. The term“alkoxy”, alone or in combination, means an alkyl ether radical whereinthe term alkyl is as defined above. Examples of suitable alkyl etherradicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, sec-butoxy, tert-butoxy and the like. The term “cycloalkyl”,alone or in combination, means a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl radical wherein each cyclicmoiety contains from about 3 to about 8 carbon atoms and is cyclic. Theterm “cycloalkylalkyl” means an alkyl radical as defined above which issubstituted by a cycloalkyl radical containing from about 3 to about 8,preferably from 3 to 6 carbon atoms. Examples of such cycloalkylradicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andthe like. The term “aryl”, alone or in combination, means a phenyl ornaphthyl radical which optionally carries one or more substituentsselected from alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano,haloalkyl and the like, such as phenyl, p-tolyl, 4-methoxyphenyl,4-(tert-butoxy)phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-hydroxyphenyl,1-naphthyl, 2-naphthyl, and the like. The term “aralkyl”, alone or incombination, means an alkyl radical as defined above in which onehydrogen atom is replaced by an aryl radical as defined above, such asbenzyl, 2-phenylethyl and the like. The term laralkoxy carbonyll, aloneor in combination, means a radical of the formula —C(O)—O—aralkyl inwhich the term “aralkyl” has the significance given above. An example ofan aralkoxycarbonyl radical is benzyloxycarbonyl. The term aryloxy,means a radical of the formula aryl —O— in which the term aryl has thesignificance given above. The term “alkanoyl”, alone or in combination,means an acyl radical derived from an alkanecarboxylic acid whereinalkane means a radical as defined above for alkyl. Examples of alkanoylradicals include acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl,and the like. The term ocycloalkylcarbonyll means an acyl group derivedfrom a monocyclic or bridged cycloalkanecarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.The term laralkanoyll means an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl,4-methoxyhydrocinnamoyl,and the like. The term “aroyl” means an acyl radical derived from anaromatic carboxylic acid. Examples of such radicals include aromaticcarboxylic acids, an optionally substituted benzoic or naphthoic acidsuch as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl,4-(benzyloxycarbonyl)benzoyl, 1-naphthoyl, 2-naphthoyl, 6-carboxy-2naphthoyl, 6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.The heterocyclyl or heterocycloalkyl portion of a heterocyclylcarbonyl,heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, or heterocyclyalkylgroup or the like is a saturated or partially unsaturated monocyclic,bicyclic or tricyclic heterocycle which contains one or more heteroatoms selected from nitrogen, oxygen and sulphur, which is optionallysubstituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo,and the like, and/or on a secondary nitrogen atom (i.e., —NH—) by alkyl,aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiarynitrogen atom (i.e. =N—) by oxido and which is attached via a carbonatom. The heteroaryl portion of a heteroaroyl, heteroaryloxycarbonyl, ora heteroaralkoxy carbonyl group or the like is an aromatic monocyclic,bicyclic, or tricyclic heterocycle which contains the hetero atoms andis optionally substituted as defined above with respect to thedefinition of heterocyclyl. Such heterocyclyl and heteroaryl radicalshave from four to about 12 ring members, preferably from 4 to 10 ringmembers. Examples of such heterocyclyl and heteroaryl groups arepyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl,pyrrolyl, imidazolyl (e.g., imidazol 4-yl,1-benzyloxycarbonylimidazol-4-yl, etc.), pyrazolyl, pyridyl, pyrazinyl,pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyl(e.g., 2-indolyl, etc.), quinolinyl, (e.g., 2-quinolinyl, 3-quinolinyl,1-oxido-2-quinolinyl, etc.), isoquinolinyl (e.g., 1-isoquinolinyl,3-isoguinolinyl, etc.), tetrahydroquinolinyl (e.g.,1,2,3,4-tetrahydro-2-quinolyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl(e.g., 1,2,3,4-tetrahydro-i-oxo-isoquinolinyl, etc.), quinoxalinyl,9-carbolinyl, 2-benzofurancarbonyl, 1-,2-,4- or 5-benzimidazolyl, andthe like. The term “cycloalkylalkoxycarbonyl” means an acyl groupderived from a cycloalkylalkoxycarboxylic acid of the formulacycloalkylalkyl-O-COOH wherein cycloalkylalkyl has the significancegiven above. The term “aryloxyalkanoyl” means an acyl radical of theformula aryl-0-alkanoyl wherein aryl and alkanoyl have the significancegiven above. The term “heterocyclyloxycarbonyl” means an acyl groupderived from heterocyclyl-O-COOH wherein heterocyclyl is as definedabove. The term “heterocyclylalkanoyl” is an acyl radical derived from aheterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl hasthe significance given above. The term “heterocyclylalkoxycarbonyl”means an acyl radical derived from a heterocyclyl-substitutedalkane-O-COOH wherein heterocyclyl has the significance given above. Theterm “heteroaryloxycarbonyl” means an-acyl radical derived from acarboxylic acid represented by heteroaryl-O-COOH wherein heteroaryl hasthe significance given above. The term laminocarbonyll alone or incombination, means an amino-substituted carbonyl (carbamoyl) groupderived from an amino-substituted carboxylic acid wherein the aminogroup can be a primary, secondary or tertiary amino group containingsubstituents selected from hydrogen, and alkyl, aryl, aralkyl,cycloalkyl, cycloalkylalkyl radicals and the like. The term“aminoalkanoyl” means an acyl group derived from an amino-substitutedalkanecarboxylic acid wherein the amino group can be a primary,secondary or tertiary amino group containing substituents selected fromhydrogen, and alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicalsand the like. The term “halogen” means fluorine, chlorine, bromine oriodine. The term “haloalkyl” means an alkyl radical having thesignificance as defined above wherein one or more hydrogens are replacedwith a halogen. Examples of such haloalkyl radicals includechloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1,1,1-trifluoroethyl and the like. The term “leavinggroup” generally refers to groups readily displaceable by a nucleophile,such as an amine, a thiol or an alcohol nucleophile. Such leaving groupsare well known in the art. Examples of such leaving groups include, butare not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole,halides, triflates, tosylates and the like. Preferred leaving groups areindicated herein where appropriate.

Procedures for preparing the compounds of Formula I are set forth below.It should be noted that the general procedure is shown as it relates topreparation of compounds having the specified stereochemistry, forexample, wherein the absolute stereochemistry about the hydroxyl groupis designated as (R), which is the preferred stereochemistry for thecompounds of the present invention. However, such procedures aregenerally applicable to those compounds of opposite configuration, e.g.,where the stereochemistry about the hydroxyl group is (S). In addition,the compounds having the (R) stereochemistry can be utilized to producethose having the (S) stereochemistry. For example, a compound having the(R) stereochemistry can be inverted to the (S) stereochemistry usingwell-known methods.

Preparation of Compounds of Formula I

The compounds of the present invention represented by Formula I abovecan be prepared utilizing the following general procedure. Thisprocedure is schematically shown in the following Schemes I-V:

An N-protected chloroketone derivative of an amino acid having theformula:

wherein P represents an amino protecting group, and R² is as definedabove, is reduced to the corresponding alcohol utilizing an appropriatereducing agent. Suitable amino protecting groups are well known in theart and include carbobenzoxy, t-butoxycarbonyl, and the like. Apreferred amino protecting group is carbobenzoxy. A preferredN-protected chloroketone is N-benzyloxycarbonyl-L-phenylalaninechloromethyl ketone. A preferred reducing agent is sodium borohydride.The reduction reaction is conducted at a temperature of from −10° C. toabout 25° C., preferably at about 0° C., in a suitable solvent systemsuch as, for example, tetrahydrofuran, and the like. The N-protectedchloroketones are commercially available, e.g., such as from Bachem,Inc., Torrance, Calif. Alternatively, the chloroketones can be preparedby the procedure set forth in S. J. Fittkau, J. Prakt. Chem., 3, 1037(1973), and subsequently N-protected utilizing procedures which are wellknown in the art.

The halo alcohol can be utilized directly, as described below, or,preferably, is then reacted, preferably at room temperature, with asuitable base in a suitable solvent system to produce an N-protectedamino epoxide of the formula:

wherein P and R² are as defined above. Suitable solvent systems forpreparing the amino epoxide include ethanol, methanol, isopropanol,tetrahydrofuran, dioxane, and the like including mixtures thereof.Suitable bases for producing the epoxide from the reduced chloroketoneinclude potassium hydroxide, sodium hydroxide, potassium t-butoxide, DBUand the like. A preferred base is potassium hydroxide.

Alternatively, a protected amino epoxide can be prepared starting withan L-amino acid which is reacted with a suitable amino-protecting groupin a suitable solvent to produce an amino-protected L-amino acid esterof the formula:

wherein P¹ and p² independently represent hydrogen, benzyl andamino-protecting groups (as defined above), provided that P² and p² arenot both hydrogen; p³ represents carboxyl-protecting group, e.g.,methyl, ethyl, benzyl, tertiary-butyl and the like; and R² is as definedabove.

The amino-protected L-amino acid ester is then reduced, to thecorresponding alcohol. For example, the amino-protected L-amino acidester can be reduced with diisobutylaluminum hydride at −78° C. in asuitable solvent such as toluene. The resulting alcohol is thenconverted, for example, by way of a Swern oxidation, to thecorresponding aldehyde of the formula:

wherein p¹, p² and R² are as defined above. Thus, a dichloromethanesolution of the alcohol is added to a cooled (−75 to −68° C.) solutionof oxalyl chloride in dichloromethane and DMSO in dichloromethane andstirred for 35 minutes.

The aldehyde resulting from the Swern oxidation is then reacted with ahalomethyllithium reagent, which reagent is generated in situ byreacting an alkyllithium or arylithium compound with a dihalomethanerepresented by the formula X¹CH₂X² wherein X¹ and X² independentlyrepresent I, Br or Cl. For example, a solution of the aldehyde andchloroiodomethane in THF is cooled to −78° C. and a solution ofn-butyllithium in hexane is added. The resulting product is a mixture ofdiastereomers of the corresponding amino-protected epoxides of theformulas:

The diastereomers can be separated e.g., by chromatography, or,alternatively, once reacted in subsequent steps the diastereomericproducts can be separated. For compounds having the (S) stereochemistry,a D-amino acid can be utilized in place of the L-amino acid.

The amino epoxide is then reacted, in a suitable solvent system, with anequal amount, or preferably an excess of, a desired amine of theformula:

R³NH2

wherein R³ is hydrogen or is as defined above. The reaction can beconducted over a wide range of temperatures, e.g., from about 10° C. toabout 100° C., but is preferably, but not necessarily, conducted at atemperature at which the solvent begins to reflux. Suitable solventsystems include protic, non-protic and dipolar aprotic organic solventssuch as, for example, those wherein the solvent is an alcohol, such asmethanol, ethanol, isopropanol, and the like, ethers such astetrahydrofuran, dioxane and the like, and toluene,N,N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof. Apreferred solvent is isopropanol. Exemplary amines corresponding to theformula R³NH₂ include benzyl amine, isobutylamine, n-butyl amine,isopentyl amine, isoamylamine, cyclohexanemethyl amine, naphthylenemethyl amine and the like. The resulting product is a 3-(N-protectedamino)-3-(R²)-1-(NHR³)-propan-2-ol derivative (hereinafter referred toas an amino alcohol) can be represented by the formulas:

wherein P, P¹, p², R² and R³ are as described above. Alternatively, ahaloalcohol can be utilized in place of the amino epoxide.

The amino alcohol defined above is then reacted in a suitable solventwith a sulfamoyl halide, e.g. sulfamoyl chloride [R⁸(CH₂)_(n)C(R⁷R⁷′)[[R⁴]NSO₂Cl or sulfamoyl anhydride in the presence of an acid scavenger.Suitable solvents in which the reaction can be conducted includemethylene chloride, tetrahydrofuran. Suitable acid scavengers includetriethylamine, pyridine. The resulting sulfamic acid derivative can berepresented, depending on the epoxide utilized, by the formulas;

wherein P, P¹, P², R², R³, R⁵, R⁷, R⁷′, R⁸ and n are as defined above.These intermediates are useful for preparing inhibitor compounds of thepresent invention and are also active inhibitors of retroviralproteases.

The sulfamoyl halides of the formula [R⁸(CH₂)_(n)C(R⁷R⁷′)]R^(4])NSO₂X,wherein R4 is hydrogen can be prepared by the reaction of a suitableisocyanate of the formula [R⁸ (CH₂)_(n)C(R⁷R⁷′)R⁴]NCR with fumingsulfuric acid to produce the corresponding sulfamate which is thenconverted to the halide by well known procedures, such as by treatingthe sulfamate with PCl₅. Alternatively the isocyanate can be treatedwith chlorosulfonic acid to produce the corresponding sulfamoyl chloridedirectly.

The sulfamoyl halides of the formula [R⁸(CH₂)_(n)C(R⁷R⁷′) ][R⁴]NSO₂Cl,wherein R⁴ is other than hydrogen, can be prepared by reacting an amineof the formula [R⁸(CH₂)_(n)C(R⁷R⁷′) ][R⁴]NH, preferably as a salt suchas the hydrochloride, with sulfuryl chloride in a suitable solvent suchas acetonitrile. The reaction mixture is gradually warmed to refluxtemperature and maintained at the reflux temperature until the reactionis complete. Alternatively, sulfamoyl halides of the formula[R⁸(CH₂)_(n)C(R⁷R⁷′) ][R⁴]NSO₂Cl can be prepared by reacting an amine ofthe fomula [R⁸(CH₂)_(n)C(R⁷R⁷R⁷′)][R⁴]NH with sulfuryl chloride inboiling MeCN as disclosed in Matier et al., J. Med. Chem., la, No. 5,p.538 (1972).

Alternatively, the sulfamoyl halide can be prepared by reacting asulfamoyl halide derivative of an isocyanate, i.e., a derivative of theformula ClSO₂NCO with an appropriate alcohol of the formulaHOC(R⁷R⁷,)(CH₂)_(n)R⁸ to produce the corresponding compound of theformula ClSO₂NHC(O)OC (R⁷R⁷′)(CH₂)_(n)R⁸. Following deletion of thecarbonyl moiety a sulfamoyl halide of the formulaClSO₂NHC(R⁷R⁷′)(CH₂)_(n)R⁸ is produced. This procedure is described inJ. or=. Chem., 54, 5826-5828 (1989). Alternatively, the amino alcoholcan be reacted with a chlorosulfonyl methyl ester of the formula ClSO₂Oalkyl to produce the corresponding derivative and then reacted with anamine of the formula HNR⁴R⁵.

Following preparation of the sulfonyl urea derivative, the aminoprotecting group P or P¹ and p² amino protecting groups are removedunder conditions which will not affect the remaining portion of themolecule. These methods are well known in the art and include acidhydrolysis, hydrogenolysis and the like. A preferred method involvesremoval of the protecting group, e.g., removal of a carbobenzoxy group,by hydrogenolysis utilizing palladium on carbon in a suitable solventsystem such as an alcohol, acetic acid, and the like or mixturesthereof. Where the protecting group is a t-butoxycarbonyl group, it canbe removed utilizing an inorganic or organic acid, e.g., HCl ortrifluoroacetic acid, in a suitable solvent system, e.g., dioxane ormethylene chloride. The resulting product is the amine salt derivative.Following neutralization of the salt, the amine is then reacted with anamino acid or corresponding derivative thereof represented by theformula (PN[CR¹′R¹Δ]_(t) CH(R¹)COOH) wherein t, R¹, R¹′ and R¹Δ are asdefined above, to produce the antiviral compounds of the presentinvention having the formula:

wherein t, P, R¹, R¹′, R¹Δ, R², R³, R⁴, R⁵, R⁷, R⁷, R⁸ and n are asdefined above. Preferred protecting groups in this instance are abenzyloxycarbonyl group or a t-butoxycarbonyl group. Where the amine isreacted with a derivative of an amino acid, e.g., when t=1 and R¹′ andR¹ Δ are both i, so that the amino acid is a β-amino acid, such β-aminoacids can be prepared according to the procedure set forth in acopending application, U.S. Ser. No. 07/345,808. Where t is 1, one ofR¹′ and R¹Δ is H and R¹ is hydrogen so that the amino acid is ahomo-β-amino acid, such homo-g-amino acids can be prepared by theprocedure set forth in a copending application, U.S. Ser. No.07/853,561. Where t is 0 and R¹ is alkyl, alkenyl, alkynyl, cycloalkyl,—CH₂SO₂NH_(2,) —CH₂CO₂CH₃, —CO₂CH_(3,) —CONH₂, —CH₂C(O)NHCH_(3,) —C(CH₃)₂(SH), —C(CH₃)₂(SCH₃), —C(CH₃)₂(S(O)CH₃], —C(CH₃)₂[S(O₂)CH₃], or anamino acid side chain, such materials are well known and many arecommercially available from Sigma-Aldrich.

The N-protecting group can be subsequently removed, if desired,utilizing the procedures described above, and then reacted with acarboxylate represented by the formula:

wherein R is as defined above and L is an appropriate leaving group suchas a halide. Preferably, where R¹ is a side chain of a naturallyoccurring a-amino acid, R is a 2-quinoline carbonyl group derived fromN-hydroxysuccinimide-2-quinoline carboxylate, i.e., L is hydroxysuccinimide. A solution of the free amine (or amine acetate salt) andabout 1.0 equivalent of the carboxylate are mixed in an appropriatesolvent system and optionally treated with up to five equivalents of abase such as, for example, N-methylmorpholine, at about roomtemperature. Appropriate solvent systems include tetrahydrofuran,methylene chloride or N,N-dimethylformamide, and the like, includingmixtures thereof.

Alternatively, the protected amino alcohol from the epoxide opening canbe further protected at the newly introduced amino group with aprotecting group P′ which is not removed when the first protecting P isremoved. One skilled in the art can choose appropriate combinations of Pand P′. one suitable choice is when P is Cbz and P′ is Boc. Theresulting compound represented by the formula:

can be carried through the remainder of the synthesis to provide acompound of the formula:

and the new protecting group P′ is selectively removed, and followingdeprotection, the resulting amine reacted to form the sulfamic acidderivative as described above. This selective deprotection andconversion to the sulfonyl urea derivative can be accomplished at eitherthe end of the synthesis or at any appropriate intermediate step ifdesired.

It is contemplated that for preparing compounds of the Formulas havingR⁶, the compounds can be prepared following the procedure set forthabove and, prior to coupling the sulfonamide derivative or analogthereof, e.g. coupling to the amino acid PNH(CH₂)_(t)CH(R¹)COOH, carriedthrough a procedure referred to in the art as reductive amihation. Thus,a sodium cyanoborohydride and an appropriate aldehyde or ketone can bereacted with the sulfonamide derivative compound or appropriate analogat room temperature in order to reductively aminate any of the compoundsof Formulas I-IV. It is also contemplated that where R³ of the aminoalcohol intermediate is hydrogen, the inhibitor compounds of the presentinvention wherein R³ is alkyl, or other substituents wherein the α-Ccontains at least one hydrogen, can be prepared through reductiveamination of the final product of the reaction between the amino alcoholand the amine or at any other stage of the synthesis for preparing theinhibitor compounds.

Contemplated equivalents of the general formulas set forth above for theantiviral compounds and derivatives as well as the intermediates arecompounds otherwise corresponding thereto and having the same generalproperties, such as tautomers thereof as well as compounds, wherein oneor more of the various R groups are simple variations of thesubstituents as defined therein, e.g., wherein R is a higher alkyl groupthan that indicated. In addition, where a substituent is designated as,or can be, a hydrogen, the exact chemical nature of a substituent whichis other than hydrogen at that position, e.g., a hydrocarbyl radical ora halogen, hydroxy, amino and the like functional group, is not criticalso long as it does not adversely affect the overall activity and/orsynthesis procedure.

The chemical reactions described above are generally disclosed in termsof their broadest application to the preparation of the compounds ofthis invention. occasionally, the reactions may not be applicable asdescribed to each compound included within the disclosed scope. Thecompounds for which this occurs will be readily recognized by thoseskilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to thoseskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilypreparable from known starting materials.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

All reagents were used as received without purification. All proton andcarbon NMR spectra were obtained on either a Varian VXR-300 or VXR-400nuclear magnetic resonance spectrometer.

The following Examples 1 through 9 illustrate preparation ofintermediates. These intermediates are useful in preparing the inhibitorcompounds of the present invention as illustrated in Examples 13-17. Inaddition, the intermediates of Examples 4-9 are also retroviral proteaseinhibitors and inhibit, in particular, HIV protease.

EXAMPLE 1

Preparation ofNr3(S)-benzvloxvcarbonylamino-2(R)-hvdroxy-4-phenvlbutvll-N-isoamylamine

Part A:

To a solution of 75.Og (0.226 mol) ofN-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of807 mL of methanol and 807 mL of tetrahydrofuran at −20° C., was added13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borohydride over onehundred minutes. The solvents were removed under reduced pressure at 40°C. and the residue dissolved in ethyl acetate (approx. IL). The solutionwas washed sequentially with IM potassium hydrogen sulfate, saturatedsodium bicarbonate and then saturated sodium chloride solutions. Afterdrying over anhydrous magnesium sulfate and filtering, the solution wasremoved under reduced pressure. To the resulting oil was added hexane(approx. 1L) and the mixture warmed to 60° C. with swirling. Aftercooling to room temperature, the solids were collected and washed with2L of hexane. The resulting solid was recrystallized from hot ethylacetate and hexane to afford 32.3 g (43% yield) ofN-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp150-151° C. and M+Li⁺=340.

Part B:

To a solution of 6.52 g (0.116 mol, 1.2 equiv.) of potassium hydroxidein 968 mL of absolute ethanol at room temperature, was added 32.3 g(0.097 moll of N-CBZ-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol. Afterstirring for fifteen minutes, the solvent was removed under reducedpressure and the solids dissolved in methylene chloride. After washingwith water, drying over magnesium sulfate, filtering and stripping, oneobtains 27.9 g of a white solid. Recrystallization from hot ethylacetate and hexane afforded 22.3 g (77% yield) ofN-benzyloxycarbonyl-3(S)-amino-1,2(S)-epoxy-4-phenylbutane, mp 102-103°C. and MH⁺298.

Part C:

A solution of N-benzyloxycarbonyl3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (1.00 g, 3.36 mmol) andisoamylamine (4.90 g, 67.2 mmol, 20 equiv.) in 10 mL of isopropylalcohol was heated to reflux for 1.5 hours. The solution was cooled toroom temperature, concentrated in vacuo and then poured into 100 mL ofstirring hexane whereupon the product crystallized from solution. Theproduct was isolated by filtration and air dried to give 1.18 g, 95% ofN=[]3(S)-phenylmethylcarbamoyl)amino-2(R)-hydroxy-4-phenylbutyl[N-](3-methylbutyl))aminemp 108.0-109.5° C., MH⁺m/z =371.

EXAMPLE 2

Pretparation of N,N-dibenzvl-3(S)-amino-1.2-(S)-etooxv-4-phenylbutane

Step A:

A solution of L-phenylalanine (50.0 g, 0.302 mol), sodium hydroxide(24.2 g, 0.605 mol) and potassium carbonate (83.6 g, 0.605 mol) in water(500 ml) is heated to 97° C. Benzl bromide (108.5 ml, 0.912 mol) is thenslowly added (addition time −25 min). The mixture is then stirred at 97°C. for 30 minutes. The solution is cooled to room temperature andextracted with toluene (2×250 ml). The combined organic layers are thenwashed with water, brine, dried over magnesium sulfate, filtered andconcentrated to give an oil product. The crude product is then used inthe next step without purification.

The crude benzylated product of the above step is dissolved in toluene(750 ml) and cooled to −55° C. A 1.5 M solution of DIBAL-H in toluene(443.9 ml, 0.666 mol) is then added at a rate to maintain thetemperature between −55° to −50° C. (addition time —1 hour). The mixtureis stirred for 20 minutes at −55° C. The reaction is quenched at −55° C.by the slow addition of methanol (37 ml). The cold solution is thenpoured into cold (5° C.) 1.5 N HCl solution (1.8 L). The precipitatedsolid (approx. 138 g) is filtered off and washed with toluene. The solidmaterial is suspended in a mixture of toluene (400 ml) and water (100ml). The mixture is cooled to 5° C., treated with 2.5 N NaOH (186 ml)and then stirred at room temperature until the solid is dissolved. Thetoluene layer is separated from the aqueous phase and washed with waterand brine, dried over magnesium sulfate, filtered and concentrated to avolume of 75 ml (89 g). Ethyl acetate (25 ml) and hexane (25 ml) arethen added to the residue upon which the alcohol product begins tocrystallize. After 30 min., an additional 50 ml hexane is added topromote further crystallization. The solid is filtered off and washedwith 50 ml hexane to give approximately 35 g of material. A second cropof matrial can be isolated by refiltering the mother liquor. The solidsare combined and recrystallized from ethyl acetate (20 ml) and hexane(30 ml) to give, in 2 crops, approximately 40 g (40% fromL-phenylalanine) of analytically pure alcohol product. The motherliquors are combined and concentrated (34 g). The residue is treatedwith ethyl acetate and hexane which provides an additional 7 g (-7%yield) of slightly impure solid product. Further optimization in therecovery from the mother liquor is probable.

Step C:

A solution of oxalyl chloride (8.4 ml, 0.096 mol) in dichloromethane(240 ml) is cooled to −74° C. A solution of DMSO (12.0 ml, 0.155 mol) indichloromethane (50 ml) is then slowly added at a rate to maintain thetemperature at −74° C. (addition time ˜1.25 hr). The mixture is stirredfor 5 min. followed by addition of a solution of the alcohol (0.074 mol)in 100 ml of dichloromethane (addition time −20 min., temp. −75° C. to−68° C.). The solution is stirred at −78° C. for 35 minutes.Triethylamine (41.2 ml, 0.295 mol) is then added over 10 min. (temp.−78° to −68° C.) upon which the ammonium salt precipitated. The coldmixture is stirred for 30 min. and then water (225 ml) is added. Thedichloromethane layer is separated from the aqueous phase and washedwith water, brine, dried over magnesium sulfate, filtered andconcentrated. The residue is diluted with ethyl acetate and hexane andthen filtered to further remove the ammonium salt. The filtrate isconcentrated to give the desired aldehyde product. The aldehyde wascarried on to the next step without purification.

Temperatures higher than −70° C. have been reported in the literaturefor the Swern oxidation. Other Swern modifications and alternatives tothe Swern oxidations are also possible.

A solution of the crude aldehyde 0.074 mol and chloroiodomethane (7.0ml, 0.096 mol) in tetrahydrofuran (285 ml) is cooled to −78° C. A 1.6 Msolution of n-butyllithium in hexane (25 ml, 0.040 mol) is then added ata rate to maintain the temperature at −75° C. (addition time —15 min.).After the first addition, additional chloroiodomethane (1.6 ml, 0.022mol) is added again, followed by n-butyllithium (23 ml, 0.037 mol),keeping the temperature at −75° C. The mixture is stirred for 15 min.Each of the reagents, chloroiodomethane (0.70 ml, 0.010 mol) andn-butyllithium (5 ml, 0.008 mol) are added 4 more times over 45 min. at−75° C. The cooling bath is then removed and the solution warmed to 22°C. over 1.5 hr. The mixture is poured into 300 ml of saturated aq.ammonium chloride solution. The tetrahydrofuran layer is separated. Theaqueous phase is extracted with ethyl acetate (1×300 ml). The combinedorganic layers are washed with brine, dried over magnesium sulfate,filtered and concentrated to give a b rown oil (27.4 g). The productcould be used in the next step without purification. The desireddiastereomer can be purified by recrystallization at a subsequent step.

Alternately, the product could be purified by chromatography.

EXAMPLE 3

Preparation ofNf3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylIN-isobutylamine

A solution of N-benzyloxycarbonyl-3(S)-amino-1,2-(S)-epoxy-4-phenylbutane (50.0 g, 0.168 mol) and isobutylamine (246 g, 3.24 mol, 20equivalents) in 650 mL of isopropyl alcohol was heated to reflux for1.25 hours. The solution was cooled to room temperature, concentrated invacuo and then poured into 1 L of stirring hexane whereupon the productcrystallized from solution. The product was isolated by filtration andair dried to give 57.56 g, 92% ofN[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenyl]N-isobutylamine, mp108.0-109.5° C., MH+m/z=371.

EXAMPLE 4

Preparation of Sulfamoyl Chlorides

Method A:

An amino acid ester hydrochloride (1 mmol) is suspended in a suitablesolvent such as hexane, dichloromethane, toluene and the like, but mostpreferable acetonitrile. To the well stirred mixture is added sulfurylchloride (3 mmol) in a suitable solvent, or neat, dropwise over severalminutes. The reaction is allowed to stir at zero to reflux temperatures,preferable at reflux, for 1 to 48 hours, preferably for 24 hours. Thesolvent is removed and the residue triturated with a suitable solvent,such as hexane, pentane, toluene, but most preferably diethyl ether. Thesolvent is decanted and concentrated. The product may then be utilizedas such or purified by distillation or in the case of solidsrecrystallized from appropriate solvents.

Method B:

An alpha-hydroxy ester (1 mmol) is dissolved in an appropriate solventsuch as acetonitrile, dichloromethane, toluene and the like, but mostpreferable hexane. Chlorosulfonyl isocyanate (1 mmol) added neat or in asolvent, preferably in hexane, is added dropwise. The reaction isstirred from zero to reflux, preferably at reflux, for 5 minutes toseveral hours, preferably for 1 hour. The solvent is then removed andthe residue used as such, or taken up in an appropriate solvent,expecially dichloromethane, and filtered to remove any impurities. Theproduct may then be purified by distillation or in the case of solidsrecrystallized from appropriate solvents.

EXAMPLE 5

Preparation of Sulfamates

An amino alcohol as prepared in Example 3 (1 mmol) and a suitable base,such as triethylamine, pyridine, sodium carbonate, and the like,preferably diisopropylethylamine (1 mmol) are dissolved in a suitablesolvent such as ether, chloroform, acetronitrile and the like, butpreferably dichloromethane. The sulfamoyl chloride from part A or B ofExample 4, neat or dissolved in an appropriate solvent, is added to theabove solution. The reaction is stirred at zero to reflux temperatures,but preferably at room temperature for 1 to 48 hours. The product can bepurified by silica gel chromatography or by an extractive workupfollowed by recrystallization.

The following Examples 6-8 illustrate preparation of β-amino acidintermediates. These intermediates can be coupled to the intermediatecompounds illustrated by those of Examples 4 and 5 to produce inhibitorcompounds of the present invention containing β-amino acids.

EXAMPLE 6

A. Preparation of 4(4-methoxybenzyl)itaconate

A 5 L three-necked round bottomed flask equipped with constant pressureaddition funnel, reflux condenser, nitrogen inlet, and mechanicalstirrer was charged with itaconic anhydride (660.8 g, 5.88 mol) andtoluene (2300 mL). The solution was warmed to reflux and treated with4-methoxybenzyl alcohol (812.4 g, 5.88 mol) dropwise over a 2.6 hperiod. The solution was maintained at reflux for an additional 1.5 hand then the contents were poured into three 2 L erlenmeyer flasks tocrystallize. The solution was allowed to cool to room temperaturewhereupon the desired mono-ester crystallized. The product was isolatedby filtration on a Buchner funnel and air dried to give 850.2 g, 58% ofmaterial with mp 83-85° C., a second crop, 17% was isolated aftercooling of the filtrate in an ice bath. ¹H NMR (CDCl₃) 300 MHz 7.32(d,J=8.7 Hz, 2H), 6.91(d, J=8.7 Hz, 2H), 6.49(s, 1H), 5.85(s, 1H), 5.12(s,2H), 3.83(s, 3x), 3.40(s, 2H).

B. Preparation of Methyl 4(4-methoxybenzyl) itaconate

A 5 L three-necked round bottomed flask equipped with reflux condenser,nitrogen inlet, constant pressure addition funnel and mechanical stirrerwas charged with 4(4-methoxybenzyl) itaconate (453.4 g, 1.81 mol) andtreated with 1, 5-diazabicyclo [4.3.0]non-5-ene (275.6 g, 1.81 mol),(DBN), dropwise so that the temperature did not rise above 15° C. Tothis stirring mixture was added a solution of methyl iodide (256.9 g,1.81 mol) in 250 mL of toluene from the dropping funnel over a 45 mperiod. The solution was allowed to warm to is room temperature andstirred for an additional 3.25 h.

The precipitated DBN hydroiodide was removed by filtration, washed withtoluene and the filtrate poured into a separatory funnel. The solutionwas washed with sat. aq. NaHCO₃ (2×500 mL), 0.2N HCl (1×500 mL), andbrine (2×500 mL), dried over anhyd. MgSo_(4,) filtered, and the solventremoved ja vacuo. This gave a clear colorless oil, 450.2 g, 94% whoseNMR was consistent with the assigned structure. ¹H NMR (CDC13) 300 MHz7.30(d, J=8.7 Hz, 2H), 6.90(d, J=8.7 Hz, 2H), 6.34(s, 1H), 5.71(s, 1H),5.09(s, 2H), 3.82(s, 3R), 3.73(s, 3H), 3.38(s, 2H). ¹3c Nm (CDC13)170.46, 166.47, 159.51, 133.55, 129.97, 128.45, 127.72, 113.77, 66.36,55.12, 51.94, 37.64.

C. Preparation of Methyl 4(4-methoxybenzyl) 2(R)-methylsuccinate

A 500 mL Fisher-Porter bottle was charged with methyl 4(4-methoxybenzyl)itaconate (71.1 g, 0.269 mol), rhodium (R,R) DiPAMP catalyst (204 mg,0.269 mmol, 0.1 mol%) and degassed methanol (215 mL). The bottle wasflushed 5 times with nitrogen and 5 times with hydrogen to a finalpressure of 40 psig. The hydrogenation commenced immediately and afterca. 1 h the uptake began to taper off, after 3 h the hydrogen uptakeceased and the bottle was flushed with nitrogen, opened and the contentsconcentrated on a rotary evaporator to give a brown oil that was takenup in boiling iso-octane (ca. 200 mL, this was repeated twice), filteredthrough a pad of celite and the filtrate concentrated a v to give 66.6g, 93% of a clear colorless oil, ¹H NMR (CDCl₃ 300 MHz 7.30(d, J=8.7 Hz,2H), 6.91(d, J=8.7 Hz, 2H), 5.08(s, 2H), 3.82(s, 3H), 3.67(s, 3H),2.95(ddq, J=5.7, 7.5, 8.7 Hz, 1H), 2.79(dd, J=8.1, 16.5 Hz, 1H),2.45(dd, J=5.7, 16.5 Hz, 1H), 1.23(d, J=7.5 Hz, 3H).

D. Preparation of Methyl 2(R)-methylsuccinate

A 3 L three-necked round-bottomed flask equipped with a nitrogen inlet,mechanical stirrer, reflux condenser and constant pressure additionfunnel was charged with methyl 4(4-methoxybenzyl) 2(R)-methylsuccinate(432.6 g, 1.65 mol) and toluene (1200 mL). The stirrer was started andthe solution treated with trifluoroacetic acid (600 mL) from thedropping funnel over 0.25 h. The solution turned a deep purple color andthe internal temperature rose to 45° C. After stirring for 2.25 h thetemperature was 27° C. and the solution had acquired a pink color. Thesolution was concentrated on a rotary evaporator. The residue wasdiluted with water (2200 mL) and sat. aq. NaHCO_(3.)(1000 mL).Additional NaHCO₃ was added until the acid had been neutralized. Theaqueous phase was extracted with ephyl acetate (2×1000 mL) to remove theby-product and the aqueous layer was acidified to pH=1.8 with conc. HCThis so was extracted with ethyl acetate (4×), with brine, dried overanhyd. MgSO_(4,) filtered and concentrated on a rotary evaporator togive a colorless liquid 251 g, >100% that was vacuum distilled through ashort path apparatus cut 1: bath temperature 120° C. @>1 rm, bp 25-29°C.; cut 2: bath temperature 140° C. @ 0.5 mm, bp 95-108° C., 151 g, [α]d@ 25° C.=+1.38° C.(c=15.475, MeOH), [α]_(d)=+8.48° C. (neat); cut 3:bath temperature 140° C., bp 108° C., 36 g, [α]_(d)@25° C.=+1.49°C.(c=15.00, MeOH), [α]_(d) =+8.98° C. (neat). Cuts 2 and 3 were combinedto give 189 g, 78% of product, ¹H NMR (CDCl₃) 300 MHz 11.6(brs, 1H),3.72(s, 3H), 2.92(ddq, J=5.7, 6.9, 8.0 Hz, 1H), 2.81(dd, J=8.0, 16.8 Hz,1H), 2.47(dd, J=5.7, 16.8 Hz, 1H), 1.26(d, J=6.9 Hz, 3H).

E. Preparation of Methyl Itaconate

A 50 mL round bottomed flask equipped with reflux condenser, nitrogeninlet and magnetic stir bar was charged with methyl 4(4-methoxybenzyl)itaconate (4.00 g, 16 mmol), 12 mL of touluene and 6 mL oftrifluoroacetic acid. The solution was kept at room temperature for 18hours and then the volatiles were removed in The residue was taken up inethyl acetate and extracted three times with saturated aqueous sodiumbicarbonate solution. The combined aqueous extract was acidified to pH=1with aqueous potassium bisulfate and then extracted three times withethyl acetate. The combined ethyl acetate solution was washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. The residue was thenvacuum distilled to give 1.23 g, 75% of pure product, bp 85-87 @0.1 mm.¹H NMR (CDCl₃) 300 MHz 6.34(s, 1H), 5.73(s, 2H), 3.76(s, 3H), 3.38(s,2H). ¹³C NMR (CDC13) 177.03, 166.65, 129.220, 132.99, 52.27, 37.46.

F. Curtius Rogarrangement of Methyl 2(R)-methylsuccinate: Preparation ofMethyl N-Moz-α-methyl β-alanine.

A 51L four necked round bottomed flask equipped with a nitrogen inlet,reflux condenser, mechanical stirrer, constant pressure addition funnel,and thermometer adapter was charged with methyl 2(R)-methylsuccinate(184.lg, 1.26 mol), triethylamine (165.6 g, 218 mL, 1.64 mol, 1.3equivalents), and toluene (1063 mnL). The solution was warmed to 85° C.and then treated dropwise with a solution of diphenylphosphoryl azide(346.8 g, 1.26 mol) over a period of 1.2 h. The solution was maintainedat that temperature for an additional 1.0 h and then the mixture wastreated with 4-methoxybenzyl alcohol (174.1 g, 1.26 mol) over a 0.33 hperiod from the dropping funnel. The solution was stirred at 88° C. foran additional 2.25 h and then cooled to room temperature. The contentsof the flask were poured into a separatory funnel and washed with sat.aq. NaHCO₃ (2×500 mL), 0.2N HCl (2×500 mL), brine (1×500 mL), dried overanhyd. MgSO_(4,) filtered, and concentrated in vacuo to give 302.3 g,85% of the desired product as a slightly brown oil. ¹H NMR (CDCl₃) 300MHz 7.32(d, J=8.4 Hz, 2H), 6.91(d, J=8.4 Hz, 2H), 5.2(brm, 1H), 5.05(s,2H), 3.83(s, 3H), 3.70(s, 3H), 3.35(m, 2H), 2.70(m, 2H), 1.20(d, J=7.2Hz, 3H).

G. Hydrolysis of Methyl N-Moz-α-methyl pralanine: Preparation ofα-methyl β-alanine Hydrochloride

A 5 L three-necked round bottomed flask equipped with a refluxcondenser, nitrogen inlet and mechanical stirrer was charged with methylN-Moz-α-methyl β-alanine (218.6 g, 0.78 mol), glacial acetic acid (975mL) and 12N hydrochloric acid (1960 mL). The solution was then heated toreflux for 3 h. After the solution had cooled to room temperature (ca. 1h) the aqueous phase was decanted from organic residue (polymer) and theaqueous phase concentrated on a rotary evaporator. Upon addition ofacetone to the concentrated residue a slightly yellow solid formed thatwas slurried with acetone and the white solid was isolated by filtrationon a Buchner funnel. The last traces of acetone were removed byevacuation to give 97.7 g, 90% of pure product, mp 128.5-130.5° C[α]_(d) @25° C.=9.0° C. (c=2.535, Methanol). ¹H NMR (D20) 300 MHz3.29(dd, J=8.6, 13.0 Hz, 1H), 3.16(dd, J=5.0, 13.Om Hz, ¹H), 2.94(ddq,J=7.2, 5.0, 8.6 Hz, 1H), 1.30(d,J=7.2 Hz, 3H); ¹³C NMR (D₂O) 180.84,44.56, 40.27, 17.49.

H. Preparation of N-Boc α-Methyl β-Alanine

A solution of a-methyl b-alanine hydrochloride (97.7 g, 0.70 mol) inwater (1050 mL) and dioxane (1050 mL) the pH was adjusted to 8.9 with2.9N MaOH solution. This stirring solution was then treated withdi-tert-butyl pyrocarbonate (183.3 g, 0.84 mol, 1.2 equivalents) all atonce. The pH of the solution was maintained between 8.7 and 9.0 by theperiodic addition of 2.5N NaOH solution. After 2.5 h the pH hadstabilized and the reaction was judged to be complete. The solution wasconcentrated on a rotary evaporator (the temperature was maintained at<40° C.). The excess di-tert-butyl pyrocarbonate was removed byextraction with dichloromethane and then the aqueous solution wasacidified with cold lN HCl and immediately extracted with ethyl acetate(4×1000 mL). The combined ethyl acetate extract was washed with brine,dried over anhyd. MgSO_(4,) filtered and concentrated on a rotaryevaporator to give a thick oil 127.3 g, 90% crude yield that was stirredwith n-hexane whereupon crystals of pure product formed, 95.65 g, 67%,mp 76-78° C., [a]_(d)@25° C.=−11.8° C (c=2.4, EtOH). A second crop wasobtained by concentration of the filtrate and dilution with hexane, 15.4g, for a combined yield of 1 l1.05 g, 78%. ¹H NMR (acetone D₆) 300 MHz11.7 (brs, 1H), 6.05 (brs 1H), 3.35 (m, lH), 3.22 (m, 1H), 2.50 (m, 1H),1.45(s, 9H), 1.19 (d, J=7.3 Hz, 3H); ¹³C NMR (acetone D6) 177.01, 79.28,44.44, 40.92, 29.08, 15.50. Elemental analysis calc'd. for C₉H₁₇NO₄: C,53.19, H, 8.42; N, 6.89. Found: C, 53.36; H, 8.46; N, 6.99.

I. Preparation of N-4-Methoxybenzyloxycarbonyl α-Methyl β-Alanine

A solution of N-4-methoxybenzyloxycarbonyl α-methyl β-alanine methylester (2.81 g, 10.0 mmol) in 30 mL of 25% aqueous methanol was treatedwith lithium is hydroxide (1.3 equivalents) at room temperature for aperiod of 2 h. The solution was concentrated in vacuo and the residuetaken up in a mixture of water and ether and the phases separated andthe organic phase discarded. The aqueous phase was acidified withaqueous potassium hydrogen sulfate to pH=1.5 and then extracted threetimes with ether. The combined ethereal phase was washed with saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to give 2.60 g, 97% ofN-4-Methoxybenzyloxycarbonyl α-methyl β-alanine (N-Moz-AMBA) which waspurified by recrystallization from a mixture of ethyl acetate and hexaneto give 2.44 g, 91% of pure product, mp 96-97° C., MH+=268. ¹H NMR(D₆-acetone/300 MHz) 1.16 (3H, d, J=7.2Hz), 2.70 (1H, m), 3.31 (2H, m),3.31 (3H, S), 4.99 (2H, s), 6.92 (2H, 4, J=8.7 Hz), 7.13 (2H, d, J=8.7Hz).

EXAMPLE 7

Following generally the procedure of Example 6, or utilizing proceduresknown in the art, the β-amino acids set forth in Table 1 were prepared.

TABLE 1

Entry R¹ R¹′ R¹″ 1 —CH₃ H H 2 —CH(CH₃)₂ H H 3 —C(CH₃)₃ H H 4 H H H 5 H—CH₃ H 6 H —CH₃ —CH₃ 7 H H —CO2CH₃ 8 H H —CONH₂ 9 —CH₂CH₃ H H 10—CH₂CH(CH₃)₂ H H 11 —CH₂C₆H₅ H H 12

H H 13

H H 14 —CH₂COOH H H 15 H —CH(CH₃)₂ H 16 H —CH₂CH(CH₃)₂ H 17 H

H 18 H

H 19 H

H 20 H

H 21 H —(CH₂)₃CH(C₆H₅)₂ H

EXAMPLE 8

Utilizing generally the procedure set forth in Example 6, th6 followingβ-amino acid compounds were prepared.

EXAMPLE 9

N[3(s)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine(370 mg. 1.0 mmole), prepared as in Example 3, is mixed with DIEA (280μL, 2.0 mmoles) and 1.0 mmole of the sulfamoyl chloride derivative ofmethyl aminoisobutyrate (2 mmol) in a 100 mL round bottomed flaskequipped with a reflux condenser, nitrogen inlet, and magnetic stir bar.The slurry is warmed to reflux and maintained at this temperature forabout 1 hour or is stirred at room temperature for about two days.

A solution of this product (1 mmole) containing 20 mL of methanol and 5mL of acetic acid is hydrogenated over 10% palladium on carbon (80 mg)for 6 h.

The free amine (0.2 mmoles) is then coupled with N-CBZ-L-asparagine (0.3mmoles) in the presence of N-hydroxybenzotriazole (0.3 mmoles) and EDC(0.3 mmoles) to yield product.

EXAMPLE 10

Following the procedures of Examples 1-9, the compounds shown in Tables2-14 could be prepared.

TABLE 2

Entry No. R R¹ R³ R¹⁶ 1 Cbz t-Butyl i-Amyl H 2 Q t-Butyl i-Amyl Methyl 3Cbz i-Butyl i-Butyl Ethyl 4 N,N-Dimethylglycine t-Butyl i-Butyliso-Propyl 5 N,N-Dimethylglycine t-Butyl i-Butyl t-Butyl 62-Quinolinylcarbonyl CH₂C(O)NH₂ i-Butyl Benzyl 7 2-QuinolinylcarbonylCH₂C(O)NH₂ i-Butyl Methyl 8 2-Quinolinylcarbonyl CH₂C(O)NH₂ i-ButylHydrogen

TABLE 3

Entry No. R R³ R¹⁶ 1 Cbz^(a) CH₃ H 2 Cbz i-Butyl CH₃ 3 Cbz i-ButylCH₂CH₃ 4 Q^(b) i-Butyl CH(CH₃)₂ 5 Cbz i-Propyl C(CH₃)₃ 6 Q i-PropylCH₂Ph 7 Cbz C₆H₅ H 8 Cbz

CH₃ 9 Cbz

C(CH₃)₃ 10 Q

H 11 Cbz

CH₂CH₃ 12 Cbz i-Butyl C(CH₃)₃ 13 Cbz i-Butyl H 14 Cbz

CH₃ 15 Cbz

CH₂CH₃ 16 Cbz

CH(CH₃)₂ 17 Cbz i-Butyl C(CH₃)₃ 18 Cbz i-Butyl CH₂Ph 19 Cbz i-amyl H 20Q -Butyl CH₃ 21 Cbz

C(CH₃)₃ 22 Cbz (CH₂)₂CH(CH₃)₂ H 23 Q i-Butyl CH₂CH₃ 24 Cbz i-amylC(CH₃)₃ 25 Q i-Butyl H 26 Cbz

CH₃ 27 Q

CH₂CH₃ 28 Cbz —(CH₂)₂CH(CH₃)₂ CH(CH₃)₂ 29 Q —(CH₂)₂CH(CH₃)₂ C(CH₃)₃ 30Cbz —CH₂C6H₅ CH₂Ph 31 β-naphthylcarbonyl —CH₂C₆H₅ H 32 Cbz —(CH₂)₂C₆H₅CH₃ 33 Cbz —(CH₂)₂C₆H₅ C(CH₃)₃ 34 Cbz n-Butyl H 35 Cbz n-Pentyl CH₂CH₃36 Cbz n-Hexyl C(CH₃)₃ 37 Cbz

H 38 β-naphthylcarbonyl —CH₂C(CH₃)₃ CH₃ 39 β-naphthylcarbonyl—CH₂C(CH₃)₃ CH₂CH₃ 40 Cbz

CH(CH₃)₂ 41 Cbz —CH₂C₆H₅OCH₃(para) C(CH₃)₃ 42 Cbz

CH₂Ph 43 Cbz

H 44 Cbz —(CH₂)₂C(CH₃)₃ CH₃ 45 Q —(CH₂)₂C(CH₃)₃ C(CH₃)₃ 46 Cbz —(CH₂)₄OHH 47 Q —(CH₂)₄OH CH₂CH₃ 48 Q

C(CH₃)₃ 49 Q

H 50 Cbz —CH₂CH(CH₃)₂ CH₃ 51

—CH₂CH₂CH(CH₃)₂ CH₂CH₃ 52

—CH₂CH(CH₃)₂ CH(CH₃)₂ 53

—CH₂CH(CH₃)₂ C(CH₃)₃ 54

—CH₂CH(CH₃)₂ CH₂Ph 55

—CH₂CH(CH₃)₂ H 56

—CH₂CH(CH₃)₂ CH₃ 57

—CH₂CH(CH₃)₂ C(CH₃)₃ 58

—CH₂CH(CH₃)₂ H 59

—CH₂CH(CH₃)₂ CH₂CH₃ 60

—CH₂CH(CH₃)₂ C(CH₃)₃ 61

—CH₂CH(CH₃)₂ H 62

—CH₂CH(CH₃)₂ CH₃ 63

—CH₂CH(CH₃)₂ CH₂CH₃ 64

—CH₂CH(CH₃)₂ CH(CH₃)₂ 65

—CH₂CH(CH₃)₂ C(CH₃)₃ 66

—CH₂CH(CH₃)₂ CH₂Ph 67

—CH₂CH(CH₃)₂ H 68

—CH₂CH(CH₃)₂ CH₃ 69

—CH₂CH(CH₃)₂ C(CH₃)₃ 70

—CH₂Ph H 71 Q

CH₂CH₃ 72 Q

C(CH₃)₃ 73 Q

H 74 Q

CH₃ 75 Q

H 76 Q —CH₂CH═CH₂ CH₃ 77 Q

CH₂CH₃ 78 Q

CH(CH₃)₂ 79 Q —CH₂CH₂Ph C(CH₃)₃ 80 Q —CH₂CH₂CH₂CH₂OH CH₂Ph 81 Q—CH₂CH₂N(CH₃)₂ H 82 Q

CH₃ 83 Q —CH₃ C(CH₃)₃ 84 Q —CH₂CH₂CH₂SCH₃ H 85 Q —CH₂CH₂CH₂S(O)₂CH₃CH₂CH₃ 86 Q —CH₂CH₂CH₂CH(CH₃)₂ C(CH₃)₃ 87 Q —CH₂CH₂CH(CH₃)₂ H 88 Q—CH₂CH₂CH(CH₃)₂ CH₃ 89 Q —CH₂CH₂CH₂CH(CH₃)₂ CH₂CH₃ 90 Q —CH₂CH₂CH(CH₃)₂CH(CH₃)₂ 91 Q —CH₂CH₂CH(CH₃)₂ C(CH₃)₃ 92 Q —CH₂CH₂CH(CH₃)₂ CH₂Ph 93 Q—CH₂CH₂CH(CH₃)₂ H 94 β-naphthylcarbonyl —CH₂CH₂CH(CH₃)₂ H 95β-naphthylcarbonyl —CH₂CH₂CH(CH₃)₂ CH₃ 96 Q —CH₂CH(CH₃)₂ CH₂CH₃ 97β-naphthylcarbonyl —CH₂CH₂CH(CH₃)₂ CH(CH₃)₂ 98 β-naphthylcarbonyl—CH₂CH₂CH(CH₃)₂ C(CH₃)₃ 99 β-naphthylcarbonyl —CH₂CH₂CH(CH₃)₂ CH₂Ph 100β-naphthylcarbonyl —CH₂CH₂CH(CH₃)₂ H 101 β-naphthylcarbonyl—CH₂CH₂CH(CH₃)₂ CH₃ 102 Q —CH₂CH₂CH(CH₃)₂ C(CH₃)₃ 103 β-naphthylcarbonyl—CH₂CH(CH₃)₂ H 104 Q —CH₂CH(CH₃)₂ CH₂CH₃ 105 Q —CH₂CH(CH₃)₂ C(CH₃)₃ 106Q —CH₂CH₂CH₃ H 107 β-naphthylcarbonyl —CH₂CH₂CH₂CH₃ CH₃ 108 Q —CH₂CH₂CH₃CH₂CH₃ 109 Q —CH₂CH₂CH₃ CH(CH₃)₂ 110 Q —CH₂CH₂CH₃ C(CH₃)₃ 111 Q—CH₂CH₂CH₃ CH₂Ph ^(a)benzyloxycarbonyl ^(b)2-quinolinylcarbonyl

TABLE 4

n R³ R⁸ 0 —CH₂CH(CH₃)₂ —CN 0 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂ —C(O)N(CH₃)₂ 1 —CH₂CH₂CH(CH₃)₂ —CO₂CH₃ 2—CH₂CH₂CH(CH₃)₂

1

1

0 —CH₂CH₂CH(CH₃)₂

0

1

1 —CH₂CH(CH₃)₂ OH 1

OH 2

2

1

—SCH₃ 1

—SO₂CH₃ 1

—SO₂CH₃ 1 —CH₂CH(CH₃)₂ —CO₂CH₃ 1

—CO₂H 1

1

—SO₂Ph 1

—SO₂Ph 1 —CH₂CH₂CH(CH₃)₂

2 —CH₂CH₂CH(CH₃)₂ —N(CH₃)₂ 2 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂ —N(CH₃)Ph 1 —CH₂CH₂CH(CH₃)₂

1 —CH₂CH₂CH(CH₃)₂

TABLE 5

n R³ R¹⁶ 0 isoamyl CH₂CH₃ 1 isoamyl CH₂CH₃ 2 isoamyl CH₂CH₃ 3 isoamylCH₂CH₃

TABLE 6

Entry R¹ 1 CH₂SO₂CH₃ 2 (R)—CH(OH)CH₃ 3 CH(CH₃)₂ 4 (R,S)CH₂SOCH₃ 5CH₂SO₂NH₂ 6 CH₂SCH₃ 7 CH₂CH(CH₃)₂ 8 CH₂CH₂C(O)NH₂ 9 (S)—CH(OH)CH₃ 10—CH₂C≡C—H 11 —CH₂CH═CH₂ 12 —C(CH₃)₂SCH₃ 13 —C(CH₃)₂SO₂CH₃

TABLE 7

Entry R² A 1 n-Bu Cbz-Asn 2 cyclohexylmethyl Cbz-Asn 3 n-Bu Boc 4 n-BuCbz 5 C₆H₅CH₂ Boc 6 P—F—C₆H₅CH₂ Cbz 7 C₆H₅CH₂ benzoyl 8 cyclohexylmethylCbz 9 n-Bu Q-Asn 10 cyclohexylmethyl Q-Asn 11 C₆H₅CH₂ Cbz-Ile 12 C₆H₅CH₂Q-Ile 13 P—F—C₆H₅CH₂ Cbz-t-BuGly 14 C₆H₅CH₂ Q-t-BuGly 15 C₆H₅CH₂ Cbz-Val16 C₆H₅CH₂ Q-Val 17 2-naphthylmethyl Cbz-Asn 18 2-naphthylmethyl Q-Asn19 2-naphthylmethyl Cbz 20 n-Bu Cbz-Val 21 n-Bu Q-Val 22 n-Bu Q-Ile 23n-Bu Cbz-t-BuGly 24 n-Bu Q-t-BuGly 25 p-F(C₆H₄)CH₂ Q-Asn 26 p-F(C₆H₄)CH₂Cbz 27 p-F(C₆H₄)CH₂ Cbz-Asn 28 C₆H₅CH₂ Cbz-propargylglycine 29 C₆H₅CH₂Q-propargylglycine 30 C₆H₅CH₂ acetylpropargylglycine 31 n-Budimethylglycyl-t-butylglycine 32 n-Bu dimethylglycyl-isoleucine 33 n-Budimethylglycyl-valine 34 —CH₂CH₂SCH₃ dimethylglycyl-t-butylglycine 35—CH₂CH₂SCH₃ dimethylglycyl-isoleucine 36 —CH₂CH₂SCH₃dimethylglycyl-valine

TABLE 8

Entry R R¹ 1

—CH₃ 2

—CH₃ 3

—CH(CH₃)₂ 4

—CH(CH₃)₂ 5

—C(CH₃)₃ 6

—CH₃ 7

—CH₃ 8

—CH₃ 9

—CH₃ 10

—CH₃ 11

—CH₃ 12

—CH₃ 13

—CH₃ 14

—CH₃ Entry 15

16

TABLE 9

Entry R¹ R¹′ R¹″ R 1 H H H

2 H H H

3 H CH₃ H

4 H CH₃ CH₃

5 H H CO₂CH₃

6 H H H

7 H H H

8 H H CONH₂ Cbz 9 H H CONH₂ 2-quinolinylcarbonyl

TABLE 10

Entry R R′ X 1 R = H R′ = H X = H 2 R = Me R′ = Me X = H 3 R = H R′ = MeX = H 4 R = Me R′ = Me X = F 5 R = H R′ = Me X = F 6 R = Cbz R′ = Me X =H 7 R = H R′ = Bz X = H 8 R + R′ = pyrrole X = H

TABLE 11

Entry Acyl Group (R) 1 benzyloxycarbonyl 2 tert-butoxycarbonyl 3 acetyl4 2-quinoylcarbonyl 5 phenoxyacetyl 6 benzoyl 7 methyloxaloyl 8 pivaloyl9 trifluoracetyl 10 bromoacetyl 11 hydroxyacetyl 12 morpholinylacetyl 13N,N-dimethylaminoacetyl 14 N-benzylaminoacetyl 15 N-phenylaminoacetyl 16N-benzyl-N-methylaminoacetyl 17 N-methyl-N-(2-hydroxyethyl)aminoacetyl18 N-methylcarbamoyl 19 3-methylbutyryl 20 N-isobutylcarbamoyl 21succinoyl(3-carboxypropionyl) 22 carbamoyl 23 N-(2-indanyl)aminoacetyl

TABLE 12

Entry R³ R¹⁶ 1 —CH₃ H 2 -i-Butyl CH₃ 3 -i-Butyl CH₂CH₃ 4 -i-PropylCH(CH₃)₂ 5 —C₆H₅ C(CH₃)₃ 6

CH₂Ph 7

H 8

CH₃ 9 -i-Butyl C(CH₃)₃ 10 -i-Butyl H 11

CH₂CH₃ 12

C(CH₃)₃ 13

H 14 n-propyl CH₃ 15 n-propyl CH₂CH₃ 16 i-Butyl CH(CH₃)₂ 17

C(CH₃)₃ 18 (CH₂)₂CH(CH₃)₂ CH₂Ph 19 i-propyl H 20 i-propyl CH₃ 21

C(CH₃)₃ 22 —(CH₂)₂CH(CH₃)₂ H 23 —CH₂C₆H₅ CH₂CH₃ 24 —(CH₂)₂C₆H₅ C(CH₃)₃25 n-Butyl H 26 n-Pentyl CH₃ 27 n-Hexyl CH₂CH₃ 28

CH(CH₃)₂ 29 —CH₂C(CH₃)₃ C(CH₃)₃ 30

CH₂Ph 31 —CH₂C₆H₅OCH₃(para) H 32

CH₃ 33

C(CH₃)₃ 34 —(CH₂)₂C(CH₃)₃ H 35 —(CH₂)₄OH CH₂CH₃ 36

C(CH₃)₃ 37

H 38 —CH₂CH₂CH₂SCH₃ CH₃ 39 i-amyl CH₂CH₃ 40

CH(CH₃)₂ 41

CH₂C(CH₃)₃ 42 i-butyl CH₂Ph 43 —CH₂Ph —CH₂Ph 44

CH₃ 45

—CH₂Ph 46

CH₃ 47

CH₂CH₃ 48

C(CH₃)₃ 49 —CH₂CH═CH₂ H 50

CH₃ 51

CH₂CH₃ 52 —CH₂CH₂Ph CH(CH₃)₂ 53 —CH₂CH₂CH₂CH₂OH C(CH₃)₃ 54—CH₂CH₂N(CH₃)₂ CH₂Ph 55

H 56 —CH₃ CH₃ 57 —CH₂CH₂CH₂SCH₃ C(CH₃)₃ 58 —CH₂CH₂CH₂S(O)₂CH₃ H 59—CH₂CH₂CH₂CH₃ CH₂CH₃ 60 —CH₂CH₂CH₂CH₃ C(CH₃)₃ 61 —CH₂CH₂CH₂CH₃ H 62—CH₂CH₂CH₂CH₃ CH₃ 63 —CH₂CH₂CH₂CH₃ CH₂CH₃ 64 —CH₂CH₂CH₂CH₃ CH(CH₃)₂ 65—CH₂CH₂CH₂CH₃ C(CH₃)₃ 66 —CH₂CH₂CH₂CH₃ CH₂Ph 67 —CH₂CH₂CH₂CH₃ H 68—CH₂CH₂CH₂CH₃ CH₃ 69 —CH₂CH₂CH₂CH₃ C(CH₃)₃ 70 —CH₂CH₂CH₂CH₃ H 72—CH₂CH₂CH₂CH₃ CH₂CH₃ 71 —CH₂CH₂CH₂CH₃ C(CH₃)₃ 73 —CH₂CH₂CH₂CH₃

74 —CH₂CH₂CH(CH₃)₂

75 —CH₂CH(CH₃)₂

76 —CH₂CH(CH₃)₂

77 —CH₂CH(CH₃)₂

78 —CH₂CH(CH₃)₂

79 —CH₂CH₂CH₃

80 —CH₂CH₂CH₂CH₃

81 i-butyl t-butyl 82 i-amyl t-butyl 83

t-butyl 84

t-butyl

TABLE 13

Entry R¹ R¹⁶ 1 C(CH₃)₃ H 2 CH₂C≡CH CH₃ 3 C(CH₃)₂(SCH₃) CH₂CH₃ 4C(CH₃)₂(S[O]CH₃) CH(CH₃)₂ 5 C(CH₃)₂(S[O]₂CH₃) C(CH₃)₃ 6 C(CH₃)₃ CH₂Ph 7C(CH₃)₃ CH₃ 8 CH(CH₃)₂ CH₃ 9 CH(CH₂CH₃)(CH₃) C(CH₃)₃

TABLE 14

R¹ R² R³ t-Butyl Benzyl p-Fluorobenzyl i-Butyl Benzyl i-Amyl i-PropylBenzyl i-Amyl Propargyl Benzyl i-Amyl t-Butyl Benzyl i-Amyl t-ButylBenzyl Benzyl t-Butyl Benzyl n-Butyl sec-Butyl Benzyl i-AmylC(CH₃)₂(SCH₃) Benzyl i-Amyl t-Butyl p-Fluorobenzyl p-Methoxybenzyli-Butyl p-Fluorobenzyl i-Amyl i-Propyl p-Fluorobenzyl i-Amyl Propargylp-Fluorobenzyl i-Amyl t-Butyl p-Fluorobenzyl i-Amyl t-Butylp-Fluorobenzyl Benzyl t-Butyl p-Fluorobenzyl n-Butyl sec-Butylp-Fluorobenzyl i-Amyl C(CH₃)₂(SCH₃) p-Fluorobenzyl i-Amyl t-ButylCyclohexylmethyl p-Fluorobenzyl i-Butyl Cyclohexylmethyl i-Amyl i-PropylCyclohexylmethyl i-Amyl Propargyl Cyclohexylmethyl i-Amyl t-ButylCyclohexylmethyl i-Amyl t-Butyl Cyclohexylmethyl Benzyl t-ButylCyclohexylmethyl n-Butyl sec-Butyl Cyclohexylmethyl i-Amyl C(CH₃)₂(SCH₃)Cyclohexylmethyl i-Amyl t-Butyl n-Butyl Cyclohexylmethyl i-Butyl n-Butyli-Amyl i-Propyl n-Butyl i-Amyl Propargyl n-Butyl i-Amyl t-Butyl n-Butyli-Amyl t-Butyl n-Butyl Benzyl t-Butyl n-Butyl n-Butyl sec-Butyl n-Butyli-Amyl C(CH₃)₂(SCH₃) n-Butyl i-Amyl

EXAMPLE 11

The compounds of the present invention are effective HIV proteaseinhibitors. Utilizing an enzyme assay as described below, the compoundsset forth in the examples herein would be expected to inhibit the HIVenzyme. The enzyme method is described below. The substrate is2-Ile-Nle-Phe(p-NO₂)-Gln-ArgNH_(2.) The positive control is MVT-101(Miller, M. et al, Science, 1149 (1989). The assay conditions are asfollows:

Assay buffer: 20 mM sodium phosphate, pH 6.4 20% glycerol 1 mM EDTA 1 mMDTT 0.1% CHAPS

The above described substrate is dissolved in DMSO, then diluted 10 foldin assay buffer. Final substrate concentration in the assay is 80 μM.

HIV protease is diluted in the assay buffer to a final enzymeconcentration of 12.3 nanomolar, based on a molecular weight of 10,780.

The final concentration of DMSO is 14% and the final concentration ofglycerol is 18%. The test compound is dissolved in DMSO and diluted inDMSO to 10x the test concentration; lOgi of the enzyme preparation isadded, the materials mixed and then the mixture is incubated at ambienttemperature for 15 minutes. The enzyme reaction is initiated by theaddition of 40 μl of substrate. The increase in fluorescence ismonitored at 4 time points (0, 8, 16 and 24 minutes) at ambienttemperature. Each assay is carried out in duplicate wells.

EXAMPLE 12

The effectiveness of the compounds can also be determined in a CEM cellassay.

The HIV inhibition assay method of acutely infected cells is anautomated tetrazolium based calorimetric assay essentially that reportedby Pauwles et al, J. Virol. Methods, 20, 309-321 (1988). Assays can beperformed in 96-well tissue culture plates. CEM cells, a CD4+cell line,were grown in RPMI-1640 medium (Gibco) supplemented with a 10% fetalcalf serum and were then treated with polybrene (2 μg/ml). An 80 μlvolume of medium containing 1×10⁴ cells is dispensed into each well ofthe tissue culture plate. To each well is added a 100 μl volume of testcompound dissolved in tissue culture medium (or medium without testcompound as a control) to achieve the desired final concentration andthe cells are incubated at 37° C. for 1 hour. A frozen culture of HIV-1is diluted in culture medium to a concentration of 5×10⁴ TCID₅₀ per ml(TCID₅₀=the dose of virus that infects 50% of cells in tissue culture),and a 20 μL volume of the virus sample (containing 1000 TCID₅₀ of virus)is added to wells containing test compound and to wells containing onlymedium (infected control cells). Several wells receive culture mediumwithout virus (uninfected control cells). Likewise, the intrinsictoxicity of the test compound is determined by adding medium withoutvirus to several wells containing test compound. In summary, the tissueculture plates contain the following experiments:

Virus Cells Drug 1. + − − 2. + + − 3. + − + 4. + + +

In experiments 2 and 4 the final concentrations of test compounds are 1,10, 100 and 500 μg/ml. Either azidothymidine (AZT) or dideoxyinosine(ddI) is included as a positive drug control. Test compounds aredissolved in DMSO and diluted into tissue culture medium so that thefinal DMSO concentration does not exceed 1.5% in any case. DMSO is addedto all control wells at an appropriate concentration.

Following the addition of virus, cells are incubated at 37° C. in ahumidified, 5% CO₂ atmosphere for 7 days. Test compounds could be addedon days 0, 2 and 5 if desired. On day 7, post-infection, the cells ineach well are resuspended and a 100 μl sample of each cell suspension isremoved for assay. A 20 μL volume of a 5 mg/ml solution of3-(4,5-dimethylthiazol-2-yl)-2,5-dipheryltetrazolium bromide (MTT) isadded to each 100 μL cell suspension, and the cells are incubated for 4hours at 27° C. in a 5% CO₂ environment. During this incubation, MTT ismetabolically reduced by living cells resulting in the production in thecell of a colored formazan product. To each sample is added 100 μl of10% sodium dodecylsulfate in 0.01 N HCl to lyse the cells, and samplesare incubated overnight. The absorbance at 590 nm is determined for eachsample using a Molecular Devices microplate reader. Absorbance valuesfor each set of wells is compared to assess viral control infection,uninfected control cell response as well as test compound bycytotoxicity and antiviral efficacy.

The compounds of the present invention are effective antiviral compoundsand, in particular, are effective retroviral inhibitors as shown above.Thus, the subject compounds are effective HIV protease inhibitors. It iscontemplated that the subject compounds will also inhibit otherretroviruses such as other lentiviruses in particular other strains ofHIV, e.g. HIV-2, human T-cell leukemia virus, respiratory syncitialvirus, simia immunodeficiency virus, feline leukemia virus, felineimmuno-deficiency virus, hepadnavirus, cytomegalovirus and picornavirus.Thus, the subject compounds are effective in the treatment and/orproplylaxis of retroviral infections.

Compounds of the present invention can possess one or more asymmetriccarbon atoms and are thus capable of existing in the form of opticalisomers as well as in the form of racemic or nonracemic mixturesthereof. The optical isomers can be obtained by resolution of theracemic mixtures according to conventional processes, for example byformation of diastereoisomeric salts by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of Formula Iwith an optically pure acid in an activated form or an optically pureisocyanate. The synthesized diastereoisomers can be separated byconventional means such as chromatography, distillation, crystallizationor sublimation, and then hydrolyzed to deliver the enantiomerically purecompound. The optically active compounds of Formula I can likewise beobtained by utilizing optically active starting materials. These isomersmay be in the form of a free acid, a free base, an ester or a salt.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate,pectinate, persulfate, 3-phenylpro-pionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, mesylate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides, such as methyl,ethyl, propyl, and butyl chloride, bromides, and iodides; dialkylsulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides, aralkyl halides like benzyl and phenethylbromides, and others. Water or oil-soluble or dispersible products arethereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid and such organicacids as oxalic acid, maleic acid, succinic acid and citric acid. Otherexamples include salts with alkali metals or alkaline earth metals, suchas sodium, potassium, calcium or magnesium or with organic bases.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 10 mg/kg body weight daily andmore usually 0.01 to 1 mg. Dosage unit compositions may contain suchamounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex, diet andmedical condition of the patient, the severity of the disease, the routeof administration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound employed, whether a drug delivery system is utilized andwhether the compound is administered as part of a drug combination.Thus, the dosage regimen actually employed may vary widely and thereforemay deviate from the preferred dosage regimen set forth above.

The compounds of the present invention may be administered orally,parenterally, by inhalation spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches or iontophoresis devices. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more immunomodulators, antiviral agents or other antiinfectiveagents. For example, the compounds of the invention can be administeredin combination with AZT, DDI, DDC or with glucosidase inhibitors, suchas N-butyl-1-deoxynojirimycin or prodrugs thereof, for the prophylaxisand/or treatment of AIDS. When administered as a combination, thetherapeutic agents can be formulated as separate compositions Which aregiven at the same time or different times, or the therapeutic agents canbe given as a single composition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A compound represented by the formula:

or a pharmaceutically acceptable salt, or ester thereof wherein: R andR′ together with the nitrogen to which they are attached form apyrrolidinyl; R¹ represents hydrogen, —CH₂SO₂NH₂, —CH₂CO₂ CH₃, —CO₂CH₃,—CONH₂, —CH₂ C(O)NHCH₃, —C(CH₃)₂(SH), —C(CH₃)₂ (SCH₃),—C(CH₃)₂(S[O]CH₃), —C(CH₃)₂(S[O]₂CH₃), alkyl, haloalkyl, alkenyl,alkynyl and cycloalkyl radicals, and amino acid side chains selectedfrom asparagine, S-methyl cysteine and methionine and the sulfoxide (SO)and sulfone (SO₂) derivatives thereof, isoleucine, allo-isoleucine,alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine,norleucine, glutamine, threonine, glycine, allo-threonine, serine,O-alkyl serine, aspartic acid, beta-cyanoalanine and valine side chains;R² represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkylradicals, which radicals are optionally substituted with a groupselected from alkyl and halogen radials, —NO₂, —CN, —CF₃, —OR⁹ and —SR⁹,wherein R⁹ represents hydrogen and alkyl radicals, and halogen radicals;R³ represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl,alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl,heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl andmono- and disubstituted aminoalkyl radicals, wherein said substituentsare selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkylradicals, or in the case of a disubstituted aminoalkyl radical, saidsubstituents along with the nitrogen atom to which they are attached,form a heterocycloalkyl or a heteroaryl radical, and thioalkyl,alkylthioalkyl and arylthioalkyl radicals and the sulfone and sulfoxidederivatives thereof; and R⁴ represents hydrogen and radicals as definedby R³; R⁶ represents hydrogen and alkyl radicals; R⁷ and R⁷′independently represent hydrogen and radicals as defined for R³; aminoacid side chains selected from the group consisting of valine,isoleucine, glycine, alanine, allo-isoleucine, asparagine, leucine,glutamine, and t-butylglycine; radicals represented by the formulas—C(O)R¹⁶, —CO₂R¹⁶, —SO₂R¹⁶, —SR¹⁶, —CONR¹⁶R¹⁷, —CF₃ and —NR¹⁶R¹⁷; or R⁷and R⁷′ together with the carbon atom to which they are attached form acycloalkyl radical; R⁸ represents cyano, hydroxyl, alkyl, alkoxy,cycloalkyl, aryl, aralkyl, heterocycloalkyl and heteroaryl radicals andradicals represented by the formulas C(O)R¹⁶, CO₂R¹⁶, SO₂R¹⁶, SR¹⁶,CONR¹⁶R¹⁷, CF₃ and NR¹⁶R¹⁷; wherein R¹⁶ and R¹⁷ independently representhydrogen and radicals as defined for R³, or R¹⁶ and R¹⁷ together with anitrogen to which they are attached in the formula NR¹⁶R¹⁷ representheterocycloalkyl and heteroaryl radicals; x represents 1 or 2; nrepresents an integer of from 0 to
 6. 2. A compound represented by theformula:

or a pharmaceutically acceptable salt, or ester thereof wherein: R andR′ together with the nitrogen to which they are attached form apyrrolidinyl; R⁶ represents hydrogen and alkyl radicals.